Leukodystrophies and genetic leukoencephalopathies in adults: clinical, genetic and neuroimaging characterization

As leucodistrofias e as leucoencefalopatias genéticas constituem um grupo heterogêneo de doenças raras que afetam preferencialmente a substância branca encefálica, sendo mais comuns na infância. Possuem amplo espectro fenotípico, com manifestações clínicas muitas vezes inespecíficas, mais comumente sintomas neuropsiquiátricos e acometimento de tratos longos. Os achados de neuroimagem são igualmente muito heterogêneos, mas tendem a ser consistentes para cada doença individualmente, por vezes permitindo precisa correlação fenotípica-genotípica. O uso crescente das técnicas de sequenciamento de nova geração têm possibilitado a identificação das bases genéticas de muitas destas doenças e a descrição de novas entidades, principalmente na faixa etária pediátrica. Já são mais de 60 genes associados a este grupo de doenças, adicionando complexidade à abordagem destes pacientes. No entanto, ainda se conhece pouco a respeito dos fenótipos e genótipos de pacientes adultos com leucodistrofia ou leucoencefalopatia genética. O objetivo do presente estudo foi descrever aspectos clínicos, neurorradiológicos e genéticos de pacientes adultos com leucodistrofia ou leucoencefalopatia genética. Foi realizado um estudo clínico retrospectivo e parcialmente prospectivo dos pacientes em acompanhamento no nosso serviço de neurogenética. Todas as 31 famílias (38 pacientes) incluídas foram submetidas a avaliação clínica e neurorradiológica. Exames neurofisiológicos foram realizados de acordo com a apresentação clínica. Exames diagnósticos bioquímicos ou genéticos foram solicitados em três etapas sequenciais. Na primeira etapa, após avaliação clínica e de neuroimagem, os pacientes foram submetidos a avaliação bioquímica ou teste genético específico conforme a hipótese diagnóstica. Nesta etapa 13 probandos obtiveram diagnóstico definitivo - sete com adrenoleucodistrofia/adrenomieloneuropatia ligada ao X, três com acidúria L2-hidroxiglutárica, um com leucodistrofia autossômica dominante do adulto, um com doença de Alexander e um com síndrome de Sjögren-Larsson. Na segunda etapa, os pacientes foram submetidos a avaliação por sequenciamento do exoma clínico. Nesta etapa, mais 13 probandos obtiveram diagnóstico: quatro com doença de substância branca evanescente, três com CADASIL, três com leucoencefalopatia difusa hereditária com esferoides, um com leucoencefalopatia com acometimento de tronco encefálico e medula espinhal e elevação de lactato, um com a síndrome de Gordon-Holmes e um com a doença relacionada a PLP1. Na terceira etapa, os probandos sem diagnóstico foram submetidos a avaliação por sequenciamento completo do exoma e mais dois probandos obtiveram diagnóstico. Uma família foi diagnóstica com deficiência intelectual relacionada a PUS3, uma condição extremamente rara que cursa com deficiência intelectual sindrômica, leucoencefalopatia e, em nossas pacientes, nefropatia, que não havia sido previamente descrita. A outra família apresentou um fenótipo totalmente novo associado a FDX2. Os pacientes apresentavam atrofia óptica congênita, miopatia mitocondrial, polineuropatia periférica axonal e leucoencefalopatia reversível. Após as três etapas, 28 dentre 31 probandos (90%) obtiveram diagnóstico definitivo e três probandos continuaram sem diagnóstico definitivo. Concluímos que o quadro clínico e neurorradiológico das leucodistrofias e leucoencefalopatias genéticas em adultos é muito heterogêneo e depende da etiologia subjacente. A avaliação clínica e neurorradiológica minuciosas associadas a avaliação genética não enviesada, seja por sequenciamento do exoma clínico, seja por sequenciamento completo do exoma, foi determinante para o diagnóstico correto na maioria dos pacientesLeukodystrophies and genetic leukoencephalopathies are a heterogeneous group of rare disorders that affect predominantly the cerebral white matter. They are more common in children and have a wide phenotypic spectrum with non-specific clinical features dominated by neuropsychiatric manifestations and long-tract symptoms. The neuroimaging findings are highly heterogeneous, but commonly have the same features for the same disorders, allowing precise phenotypic-genotypic correlation. As next-generation sequencing techniques become widely used, the genetic basis of a great number of these disorders has been established, as new disorders have been identified, especially in the pediatric population. At least 60 genes have been associated to these disorders, adding complexity to the diagnostic approach of such patients. However, little is known about the phenotypes and the genotypes of adult patients with leukodystrophies and genetic leukoencephalopathies. The aim of the present study was to describe clinical, neuroradiological and genetic aspects of adult patients with leukodystrophy or genetic leukoencephalopathy. A retrospective and partially prospective clinical study was conducted in our neurogenetics service. All 31 families included (38 patients) were clinically and neuroradiologically evaluated. Neurophysiological studies were performed as needed. Biochemical or genetic diagnostic tests were ordered in three sequential steps. On the first step, based on the clinical and neuroradiological presentations, biochemical or single-gene test were ordered according to the diagnostic hypothesis. On this step, 13 probands had a definitive diagnosis - seven with X-linked adrenoleukodystrophy/ adrenomyeloneuropathy, three with L2-hydroxyglutaric aciduria, one with autosomal dominant adult-onset demyelinating leukodystrophy, one with Alexander disease ando ne with Sjögren-Larsson syndrome. On the second step, patients were evaluated by focused exome sequencing and 13 patients were diagnosed: four with vanishing white matter disease, three with CADASIL, three with hereditary diffuse leukoencephalopathy with spheroids, one with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, one with Gordon-Holmes syndrome and ne with PLP1-related disorder. On the third step, the probands without diagnosis were evaluated by whole-exome sequencing and two had a definitive diagnosis. One family was diagnosed with PUS3-related intellectual deficiency, an extremely rare condition that causes syndromic intellectual deficiency, leukoencepahlopathy and, in our patients, nephropathy, something that was not previously described in this condition. The other family presented a totally new phenotype associated with FDX2. The patients presented congenital optic atrophy, mitochondrial myopathy, axonal peripheral polyneuropathy and reversible leukoencephalopathy. After the three steps, 28 out of 31 probands (90%) had a definitive diagnosis and three probands, remained undiagnosed. We concluded that the clinical and neuroradiological picture of adult patients with leukodystrophies and genetic leukoencephalopathies are highly heterogeneous and depends on the specific etiology. Careful clinical and neuroradiological evaluations associated with a nonbiased genetic test - focused exome sequencing or whole-exome sequencing -, can define the correct diagnosis in a great proportion of patient

Did you rule out neurosyphilis?

Abstract -Neurosyphilis, formerly a frequent cause of dementia, is now a rare condition in developed countries. However, syphilis remains common in many developing countries, where adequate diagnosis and treatment of early syphilis may be lacking, increasing the chances of neurosyphilis and prevalence of syphilitic dementia. Objectives: To present cases of syphilitic dementia seen in a cognitive and behavioral neurology unit in Brazil, emphasizing their first symptoms and the challenges they posed in diagnosis. Methods: At our unit of the Hospital das Clínicas of the University of São Paulo, all patients are submitted to blood treponemal tests. When the test is positive, a lumbar puncture is performed. We retrospectivelly reviewed all cases of neurosyphilis seen in our unit from January 1991 to November 2009. Results: Nine cases of neurosyphilis (0.77% of the 1160 cases in our files) were identified over the period. Patients with neurosyphilis were all men, had a mean age of 47.8 (±13.0) years (median of 43 years), and presented with various neuropsychiatric syndromes and elusive diagnoses. The median time from onset of symptoms to diagnosis was 24 months and only one patient made a full recovery after treatment. Conclusions: Neurosyphilis is not frequent but remains present, causing several types of neuropsychiatric syndromes. As it is very simple to rule out neurosyphilis by performing a blood treponemal test, this test should be performed in all patients with neuropsychiatric symptoms, particularly in regions of the world where syphilis is still a commonly occurring disease. Key words: neurosyphilis, syphilis, dementia, neuropsychiatry, paretic neurosyphilis. Você excluiu neurossífilis? Resumo -Neurossífilis, anteriormente uma causa freqüente de demência, é atualmente rara nos países desenvolvidos. A sífilis é ainda uma doença comum em muitos países em desenvolvimento, onde o diagnóstico e tratamento da sífilis precoce podem não ser adequados, o que aumenta a possibilidade de ocorrência de neurossífilis e de demência. Objetivos: apresentar casos de demência sifilítica atendidos em uma unidade de neurologia cognitiva e do comportamento no Brasil, enfatizando os primeiros sintomas e os desafios que neurossífilis mediante teste treponêmico no sangue, este teste deve ser realizado em todo paciente com sintomas neuropsiquiátricos, particularmente nas regiões do mundo onde a sífilis é ainda uma doença comum

Did you rule out neurosyphilis?

Abstract -Neurosyphilis, formerly a frequent cause of dementia, is now a rare condition in developed countries. However, syphilis remains common in many developing countries, where adequate diagnosis and treatment of early syphilis may be lacking, increasing the chances of neurosyphilis and prevalence of syphilitic dementia. Objectives: To present cases of syphilitic dementia seen in a cognitive and behavioral neurology unit in Brazil, emphasizing their first symptoms and the challenges they posed in diagnosis. Methods: At our unit of the Hospital das Clínicas of the University of São Paulo, all patients are submitted to blood treponemal tests. When the test is positive, a lumbar puncture is performed. We retrospectivelly reviewed all cases of neurosyphilis seen in our unit from January 1991 to November 2009. Results: Nine cases of neurosyphilis (0.77% of the 1160 cases in our files) were identified over the period. Patients with neurosyphilis were all men, had a mean age of 47.8 (±13.0) years (median of 43 years), and presented with various neuropsychiatric syndromes and elusive diagnoses. The median time from onset of symptoms to diagnosis was 24 months and only one patient made a full recovery after treatment. Conclusions: Neurosyphilis is not frequent but remains present, causing several types of neuropsychiatric syndromes. As it is very simple to rule out neurosyphilis by performing a blood treponemal test, this test should be performed in all patients with neuropsychiatric symptoms, particularly in regions of the world where syphilis is still a commonly occurring disease. Key words: neurosyphilis, syphilis, dementia, neuropsychiatry, paretic neurosyphilis. Você excluiu neurossífilis? Resumo -Neurossífilis, anteriormente uma causa freqüente de demência, é atualmente rara nos países desenvolvidos. A sífilis é ainda uma doença comum em muitos países em desenvolvimento, onde o diagnóstico e tratamento da sífilis precoce podem não ser adequados, o que aumenta a possibilidade de ocorrência de neurossífilis e de demência. Objetivos: apresentar casos de demência sifilítica atendidos em uma unidade de neurologia cognitiva e do comportamento no Brasil, enfatizando os primeiros sintomas e os desafios que neurossífilis mediante teste treponêmico no sangue, este teste deve ser realizado em todo paciente com sintomas neuropsiquiátricos, particularmente nas regiões do mundo onde a sífilis é ainda uma doença comum

Did you rule out neurosyphilis?

Abstract Neurosyphilis, formerly a frequent cause of dementia, is now a rare condition in developed countries. However, syphilis remains common in many developing countries, where adequate diagnosis and treatment of early syphilis may be lacking, increasing the chances of neurosyphilis and prevalence of syphilitic dementia. Objectives: To present cases of syphilitic dementia seen in a cognitive and behavioral neurology unit in Brazil, emphasizing their first symptoms and the challenges they posed in diagnosis. Methods: At our unit of the Hospital das Clínicas of the University of São Paulo, all patients are submitted to blood treponemal tests. When the test is positive, a lumbar puncture is performed. We retrospectivelly reviewed all cases of neurosyphilis seen in our unit from January 1991 to November 2009. Results: Nine cases of neurosyphilis (0.77% of the 1160 cases in our files) were identified over the period. Patients with neurosyphilis were all men, had a mean age of 47.8 (±13.0) years (median of 43 years), and presented with various neuropsychiatric syndromes and elusive diagnoses. The median time from onset of symptoms to diagnosis was 24 months and only one patient made a full recovery after treatment. Conclusions: Neurosyphilis is not frequent but remains present, causing several types of neuropsychiatric syndromes. As it is very simple to rule out neurosyphilis by performing a blood treponemal test, this test should be performed in all patients with neuropsychiatric symptoms, particularly in regions of the world where syphilis is still a commonly occurring disease

A novel complex neurological phenotype due to a homozygous mutation in FDX2

Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C 4 T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis